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The importance of genetic factors in schizophrenia is clear but the mechanism involved remains obscure. Etiological heterogeneity may be responsible. Recently there has been interest in a putative distinction between genetic and environmental forms of the illness based on a positive or negative family history of the disorder. Those with a positive family history are classified as 'familial' and are considered to be more likely to have the genetic form of the illness. Those with a negative family history are classified as 'sporadic' and considered more likely to have an environmental form of the illness. This paper reports the results of a Monte Carlo simulation study with varying rates of misclassification to determine the statistical power of comparisons between familial and sporadic groups. For a large sample (n = 175) statistical power was moderate to good for effect sizes greater than or equal to 1.0 standard deviation unit and positive predictive value of 0.3 or greater.

For 2 years serum neuroleptic levels, prolactin levels, and clinical states were assessed in 105 male schizophrenic outpatients every 6 months. The patients were taking a variety of neuroleptics at clinically determined fixed doses. Those who had psychotic symptoms at 50% or more of their visits attained serum levels of neuroleptics and prolactin well within or above the range observed in the remitted patients. Neuroleptic and prolactin levels did not discriminate patients who relapsed from those who did not relapse. In the remitted patients who relapsed at least once during the study period, neuroleptic and prolactin serum levels were lower before the relapse episodes than before the stable periods.

Epidemiological studies have consistently found women to be at greater risk than men for affective disorders. This sex effect may help clarify genetic transmission and heterogeneity. Data from eight family studies of unipolar and eight family studies of bipolar probands were used to calculate family resemblance sex ratios. These observed sex ratios were then compared to sex ratios predicted by X-linked and nonfamilial effects models. Maximum likelihood estimation of competing models revealed that X linkage was not a good fit to the unipolar data. The bipolar studies were not consistent with either the X-linked or the nonfamilial effects model.

This study begins to test the hypothesis that schizophrenic men and women may be at risk for experiencing different subtypes of the illness. Given past research, hypotheses predict that schizophrenic men will have an earlier age of onset, poorer premorbid history, lower family morbid risk, and poorer course. Data consist of 332 schizophrenic patients diagnosed according to DSM-III and 713 of their first-degree relatives from the double-blind Iowa 500 and non-500 family studies. Survival analysis was used to estimate age of onset, and Strömgren's abridged method for age correction was used to estimate family morbidity risks. Findings support our hypotheses and suggest that men may be at risk for experiencing a more severe form of schizophrenia.

The single major locus (SML) model of Bucher and Elston (1981) was applied to data collected in a long-term follow-up and family study of major effective disorders. Pedigree segregation analysis was used to test the hypothesis that bipolar and unipolar disorders are phenotypic variants of the same genotype at a SML. The particular SML model examined did not adequately describe the familial pattern of these disorders in families of bipolar and unipolar probands. Although other SML models may be superior, it is likely that the existence of a SML will be obscured by genetic heterogeneity.

Serum neuroleptic levels, prolactin levels, and clinical state were assessed for 1 year in 29 schizophrenic outpatients whose clinically determined neuroleptic dose had been reduced by 50%. Fifty-five percent of the subjects remained stable. Neuroleptic dose did not differ between relapsed and stable patients. Serum prolactin (PRL) assessed 2 weeks after dose reduction and mean PRL after reduction were significantly lower among relapsers. Serum neuroleptic levels were significantly lower for relapsers in patients on haloperidol. Among relapsers, there were no serum PRL or neuroleptic level differences between stable periods and the relapse episode. Among patients with relatively low neuroleptic bioavailability, relapsers reported lower levels of social activity and had social networks that were less enjoyable, more aversive, and less helpful than those of stable patients.

Serum neuroleptic activity by radioreceptor assay and prolactin concentration were measured every 6 months for 2 years in 105 male schizophrenic outpatients. The patients took a variety of neuroleptics at clinically determined doses. As expected, when four dissimilar neuroleptics were examined together, there was no significant correlation between serum neuroleptic activity and either equivalent neuroleptic dose or serum prolactin concentration. Moderate correlations were seen, however, when neuroleptic activity was standardized between neuroleptic drugs. Similar moderate correlations were seen when neuroleptic activity was corrected for the blood-to-brain distribution of each neuroleptic. These two correction techniques ranked corrected neuroleptic activity in very similar orders. Correction for blood-to-brain distribution may be a practical way to compare serum neuroleptic activity from different neuroleptics.

A substantial number of patients do not meet diagnostic criteria for schizophrenia yet exhibit psychotic phenomena characteristic of that disorder (e.g., schizophreniform disorder, schizoaffective disorder, paranoid disorder, atypical psychosis). The relationship between schizophrenia and these disorders is poorly understood. This paper describes how the two-threshold multifactorial model of familial transmission can be applied to test the hypothesis that these disorders share a multifactorial etiology with schizophrenia. The procedure is illustrated using data from a blind family study of the major psychoses. Results support the hypothesis that the disorders under examination share a common multifactorial familial etiology. Methodological issues are discussed along with suggestions for future research in this area.

The two-threshold multifactorial polygenic (MFP) model was applied to blind family study data, collected in a long-term follow-up and family study of major affective disorders. This model tested whether bipolar and unipolar disorders are manifestations of the same underlying factors or if they are independently caused disorders. The hypothesis that bipolar and unipolar disorders are, respectively, severe and mild forms of the same disorder was supported. There was little evidence for different familial aetiologies for bipolar and unipolar disorders in our sample.